Dysmenorrhea is a term used to describe painful menstruation. The pain may range from minor cramping to intense pain accompanied by diarrhea, nausea and vomiting, with sensations of pelvic heaviness and breast fullness. Premenstrual syndrome refers to the tension accruing prior to the onset of menstruation, and is characterized by headaches, nervousness and edema. Once menstruation has begun, there is noticeable polyuria and rapid disappearance of the edema.
Pharmaceutical products for the treatment of dysmenorrhea and/or premenstrual syndrome are known in the prior art and have been marketed commercially. Thus, for example, a number of commercially available products contain a combination of acetaminophen and pamabrom or a combination of acetaminophen, pamabrom and pyrilamine maleate. Products of this character do not contain a non-steroidal anti-inflammatory agent, such as ibuprofen or aspirin, which are highly important but not optimal in relieving the symptoms of dysmenorrhea and/or premenstrual syndrome. The acetaminophen used in such products is known to be an effective analgesic but is not generally recognized as exhibiting significant anti-inflammatory properties.
There is at least one commercial product containing a non-steroidal anti-inflammatory such as aspirin that is marketed for use in treating dysmenorrhea and/or premenstrual syndrome. Disadvantageously, this product does not contain a reliably effective diuretic which, when combined with an effective NSAID, provides relief of the array of symptoms of dysmenorrhea and/or premenstrual syndrome. Thus, this product contains a mixture of aspirin, cinnamedrine and caffeine. Cinnamedrine is conventionally recognized as an antispasmodic. Caffeine, although it is recognized as a diuretic, is not a highly potent diuretic. Moreover, the latter has the disadvantage of inducing sleeplessness in the subjects to whom it is administered, an important consideration for evening utility.
Compositions for use in the treatment of dysmenorrhea, which are disclosed in European Patent Application 0 081 823, are "combinations of analgesics (including prostaglandin synthetase inhibitors such aspirin, indomethacin and ibuprofen), diuretics, antihistamines and antispasmadics." The invention of this European Patent Application is said to reside in also incorporating 5-500 mg dextromethorphan hydrochloride with one or more of: a conventional diuretic such as ammonium chloride, pamabrom and hydrochlorothiazide; a conventional antihistaminic such as pyrilamine maleate; a conventional antispasmodic, for example, cinnamedrine, or a conventional analgesic such as, for example, aspirin, acetaminophen, indomethacin, ibuprofen or naproxen.
G. F. Shah et al, Effect of Nonsteroidal Antiinflammatory Drugs (NSAIDS) on Diuretic Property of Hydrochlorothiazide, Indian J. Pharm., 17:224-8 (1985), studied the effects of several NSAIDs including ibuprofen on hydrochlorothiazide (HCTZ) induced changes in urinary volume, sodium, potassium and creatinine excretion, in conscious rats. Shah et al concluded that the diuretic effect as well as the increased urinary sodium and potassium excretion elicited by HCTZ at 2.5 and 5 mg/kg were inhibited after oral administration of NSAIDs such as indomethacin, oxyphenbutazone, ibuprofen and naproxen, in doses which inhibited the rat carrageenin induced hind paw oedema.
Shah et al reports that of the NSAIDs tested, ibuprofen was found to be the most potent in antagonizing diuretic and natriuretic activity. Thus, a dose of 12.5 mg/kg ibuprofen inhibited the diuretic activity of 5 mg/kg HCTZ, while 25 mg/kg ibuprofen significantly antagonized the diuretic activity of 10 mg/kg HCTZ. It is further seen from Table 4 of Shah et al that as the ratio of ibuprofen to HCTZ increased at a constant dose of HCTZ, there was a concomitant reduction in the diuretic activity. For example, at 10 mg/kg HCTZ, the reported diuretic activity is 2.2.+-.0.16, while at 10 mg/kg HCTZ and 25 mg/kg ibuprofen, the diuretic activity was 1.6.+-.0.07, a reduction of about 28%. Similarly, Shah et al observed like reductions in natriuretic activity.
It is noteworthy that Shah et al administered each of the ibuprofen and the HCTZ in a gum arabic suspension. As pointed out in Bowman & Rand, Textbook of Pharmacology, p. 40.10 (2nd Edition 1980), the activity of HCTZ is preparation-dependent. Accordingly, Shah et al's observations are not predictive of the performance of a tablet comprising ibuprofen and HCTZ.